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Infection and Immunity, September 1998, p. 4093-4099, Vol. 66, No. 9
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Cloned Lines of Plasmodium berghei ANKA
Differ in Their Abilities To Induce Experimental Cerebral
Malaria
Véronique
Amani,1
Mariama Idrissa
Boubou,1
Sylviane
Pied,1
Myriam
Marussig,1
David
Walliker,2
Dominique
Mazier,1 and
Laurent
Rénia1,*
INSERM U313 and Department of Parasitology,
Groupe Hospitalier Pitié-Salpêtrière, 75013 Paris, France,1 and
Department of
Genetics, Institute of Cell, Animal and Population, University of
Edinburgh, Edinburgh EH9 3JN, United
Kingdom2
Received 22 January 1998/Returned for modification 16 March
1998/Accepted 10 June 1998
 |
ABSTRACT |
Infection with Plasmodium berghei ANKA is usually
lethal. The parasite causes in some mouse strains a neurovascular
syndrome, experimental cerebral malaria (ECM), involving
immunopathological reactions. The effects on the development of ECM of
the mouse genetic background have been clearly demonstrated, but
nothing is known about the effects of the clonal diversity of the
parasite. We showed that various cloned lines derived from a polyclonal line of P. berghei ANKA caused ECM but that the extent of
ECM induction was dependent on the amount of inoculum. Subtle
differences in ECM characteristics (survival time and
hypothermia) were also observed. We also confirmed, using the 1.49L
cloned line, that the mouse genetic background strongly
affects ECM.
| |
INTRODUCTION |
The infection of some mouse
strains with the ANKA or K173 strain of Plasmodium
berghei leads to the development of a neurovascular disease,
experimental cerebral malaria (ECM), resulting in death 6 to 14 days after inoculation with the parasite. These two parasite strains
have been extensively used in experimental models for cerebral malaria
(13, 20, 38). However, in recent years the relevance of this
model system has often been called into question. It has been suggested
that the major difference between human and murine cerebral malarias is
that there is no major cerebral sequestration of parasitized
erythrocytes (PE) in the vascular endothelium of the mouse brain
(4, 45). Lymphocytes and monocytes are the major cell
populations sequestered in the venules of rodents, but recent studies
have suggested that PE can also be sequestered (8, 15, 29,
36). Margination and sequestration of mononuclear cells have also
been reported in the brains of patients who died of cerebral malaria
(35, 37).
The idea that erythrocyte sequestration is the key factor in the
pathogenesis of the human syndrome has been challenged (4, 6, 23,
33), and it has been suggested that this process is actually one
of the terminal events of cerebral malaria (33). Cytokine
induction and nitric oxide generation have also been implicated
in the pathogenesis of cerebral malaria in both humans and
rodents (5, 6). Recent studies have shown an association between tumor necrosis factor alpha (TNF-
) concentrations,
interleukin 1 (IL-1) concentrations, and disease severity (19, 30,
31). Grau et al. used a polyclonal line of P. berghei ANKA in CBA/Ca mice and monoclonal or polyclonal
antibodies to cytokines to demonstrate the involvement of gamma
interferon (IFN-
), TNF-, IL-3, and granulocyte-macrophage
colony-stimulating factor (16, 17, 20, 21). Different
results were obtained when the K173 strain of P. berghei was used in C57BL/6 mice; antibodies to IFN- and TNF- were unable to prevent ECM (10, 13). In a
recent study, Hermsen et al. reported that circulating TNF-
was not involved in the development of ECM in C57BL/6 mice
infected with P. berghei K173 (27).
This finding demonstrated the importance of defining precisely the
host-parasite combination.
The genetic backgrounds in mice (12, 21, 32, 38) and in
humans (28) affect the development of cerebral malaria, whereas there is no firm evidence as yet that clonal variation of
the parasite has any effect. In this study, we investigated the
capacity of various cloned lines of P. berghei ANKA to
cause ECM.
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MATERIALS AND METHODS |
Mice.
Six- to 8-week-old pathogen-free female C57BL/6,
BALB/c, C3H/HeN, DBA/2, and Swiss mice were purchased from Charles
River Breeding Laboratories (Saint Aubin Les Elbeuf, France). CBA/Ca (6- to 8-week-old) mice were obtained from Harlan Olac (Leicester, United Kingdom). C3H/HeJ and 129Sv/eV (6- to 8-week-old) mice were
kindly donated by P. A. Cazenave (Institut Pasteur).
Body temperature.
Body temperature was measured with a
digital thermometer (Quick-check; Polylabo, Strasbourg, France)
inserted into the rectum and read when the readout stabilized (20 s).
Parasites.
Lines 1.49L, 1.97L, 4, and 5 of P. berghei ANKA were cloned by one of us (D.W.) from an initially
polyclonal line of P. berghei ANKA obtained from M. Wéry (Institute of Tropical Medicine, Antwerp, Belgium) as
previously described (44). Cloned lines 1.49L and 1.97L were
derived from cloned line 1 and differ in the numbers of passages in
mice. The polyclonal line used in this study was obtained from G. Grau
(University of Geneva, Geneva, Switzerland). This line was derived from
the same polyclonal line of P. berghei ANKA as that
used to derive the various cloned lines and was maintained as a
stabilate in liquid nitrogen. It was passaged sequentially in OF1,
BALB/c, and CBA/Ca mice in Geneva (7, 15) and then in
C57BL/6 mice in our laboratory. Blood stages of the cloned lines
were stored as stabilates (107 or 108 PE/ml in
Alsever's solution containing 10% glycerol) in liquid nitrogen. Mice
were infected intraperitoneally (i.p.) with various doses of PE.
Parasitemia was monitored daily by counting the number of infected
cells per 2,000 erythrocytes in Giemsa-stained slides.
Disease assessment.
Mice were considered to have ECM if they
had neurological signs (ataxia, paralysis, deviation of the head, and
convulsions). Some mice were killed when they displayed clinical signs.
Brains were removed and fixed in 10% paraformaldehyde for histological examination by standard techniques to detect neurological lesions (hemorrhage, edema, and endothelial damage). The cumulative incidence of ECM was defined as the appearance of neurological signs followed by
death after P. berghei ANKA infection.
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RESULTS |
Induction of cerebral malaria by a polyclonal line of P. berghei ANKA.
We found that different aliquots of
106 PE obtained from frozen stabilates of blood from a
C57BL/6 mouse infected with a polyclonal line of P. berghei ANKA induced ECM in replicated experiments with an
efficiency of 50 to 100% (Table 1). In each experiment, the mice that
developed ECM showed neurological signs and early hypothermia (Fig.
1B) between days 6 and 12 and had about 5 to 15% parasitemia (Fig. 1C). Histological studies showed that mice with ECM had widespread damage to the microvasculature in the brain,
with edema and hemorrhage (data not shown).
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FIG. 1.
Survival (A), body temperature (B), and parasitemia (C)
after infection of 12 C57BL/6 mice with 106 PE of the
P. berghei ANKA polyclonal line. This experiment is
experiment 4 reported in Table 1. + ECM, mice with neurological signs
of ECM;  ECM, mice with no neurological signs of ECM. Mortality is
indicated at the top of panel C as the number of mice that died on that
day, and each curve represents the progression of a single mouse.
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We also found that the mouse strains from which the PE originated
affected the incidence of ECM. PE taken from C57BL/6 or
CBA/Ca mice
consistently induced ECM in a high proportion of C57BL/6
or CBA/Ca mice
but not in BALB/c mice (Table
2). PE
taken from
Swiss mice induced ECM in few C57BL/6 or CBA/Ca mice. PE
taken
from BALB/c mice did not induce ECM in C57BL/6 or BALB/c mice.
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TABLE 2.
Cumulative incidence of ECM in mouse strains infected
with the P. berghei ANKA polyclonal line
passaged in various mouse strains
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Induction of cerebral malaria by various cloned lines of
P. berghei ANKA.
The results described above
suggested that the line of P. berghei ANKA used in
these experiments contained a mixture of clones with various degrees of
virulence. They also suggested that the proportion of these clones
could be altered by the genetic background of the mouse or could differ
between mice depending on the proportions of the various clones in the
infectious inoculum or the growth capacity of each clone.
We used cloned lines derived from a polyclonal line of
P. berghei ANKA (
44) from which our own polyclonal
line was derived
(
7,
15). PE of four cloned lines were
obtained from C57BL/6
mice, and their capacity to cause ECM was
compared with that of
the polyclonal line of
P. berghei ANKA. We observed that all of
the cloned lines induced
ECM in C57BL/6 mice infected with 2 ×
10
6 PE.
However, there were differences between the cloned lines
in survival
time and the time taken to develop hypothermia and
neurological
manifestations. In a typical experiment (Table
3 and Fig.
2), cloned lines 1.97L and 4 induced ECM
in 6 to 7 days,
whereas cloned lines 1.49L and 5 induced neurological
signs over
a longer period (6 to 14 days) (Table
3). Mice died 2 days
after
the onset of neurological signs; therefore, extension of the time
taken to develop ECM manifestations led to a delay in mortality
(Fig.
2A) and in the development of hypothermia (Fig.
2B). The
time taken to
develop ECM in a single mouse strain could not be
used as a feature to
characterize a parasite cloned line, since
the values obtained were
highly variable in different experimental
inoculations with parasite
stabilates of the same or different
batches (data not shown).
Nonetheless, the proportion of mice
which developed ECM was constant
for the different clones.
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FIG. 2.
Survival (A) and cumulative percentage of C57BL/6 mice
displaying a body temperature below 35°C (B) after infection with
2 × 106 PE of four P. berghei
ANKA cloned lines. Symbols:  , line 1.49L;  , line 1.97L;  , line
4;  , line 5.
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|
All of the cloned lines produced similar parasitemia curves (Fig.
3). However, cloned lines 1.49L, 1.97L,
and 4 resulted in
lower parasitemia levels (10 to 20%) when they
induced ECM than
did cloned line 5 (20 to 40%).
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FIG. 3.
Parasitemia of C57BL/6 mice infected with four
P. berghei ANKA cloned lines. Mortality is
indicated at the top of each panel as the number of mice that died on
that day. Each curve represents the progression of a single mouse.
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|
Effects of the amount of infectious inoculum of three cloned lines
on the incidence of ECM.
We investigated the effects of the amount
of infectious inoculum of three cloned lines because it was previously
shown that this factor could affect the incidence of ECM
(9). For cloned lines 1.49L and 5, the injection of a large
or small quantity of PE resulted in a smaller proportion of mice having
ECM than for the other cloned line. For cloned line 1.97L, only a very large amount of inoculum (107 PE) affected the incidence of
ECM (Table 4).
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TABLE 4.
Effect of the amount of inoculum of the various cloned
lines of P. berghei ANKA on the cumulative
incidence of ECM in C57BL/6 micea
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|
Infection of several mouse strains with cloned line
1.49L.
We (Table 2) and others (7, 12, 18, 21, 24-26,
32, 34, 38, 41) have shown that the mouse genetic background affects the incidence of ECM caused by polyclonal P. berghei, so cloned line 1.49L (106 PE from C57BL/6
mice) was injected into various mouse strains. Some strains were very
susceptible to ECM, some were partially susceptible, and others were
not susceptible at all (Table 5). Mice
developed ECM between days 7 and 12, had moderate parasitemia at that
time, and suffered early hypothermia, which varied from a low
(BALB/c) to a high (C57BL/6) degree. Infection with cloned line 1.49L
was always lethal in all of the mouse strains and resulted in similar
parasitemia curves in all of the strains (data not shown). Mice which
did not die of ECM died of anemia and hyperparasitemia.
Effect of the mouse strain from which PE were taken on ECM
induced by P. berghei ANKA cloned line
1.49L.
The origin of the PE had an effect on the development of
ECM in recipient mice (Table 2). Three strains of mice were infected with PE taken from a C57BL/6 mouse infected with cloned line 1.49L. Infected blood was obtained from these different mouse strains, and 2 × 106 PE were injected into C57BL/6 mice.
Compared with PE taken from C57BL/6 mice, PE taken from BALB/c
mice caused less ECM and PE taken from C3H/HeJ mice caused
more ECM (Table 6).
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TABLE 6.
Cumulative incidence of ECM in C57BL/6 mice infected
with P. berghei ANKA cloned line 1.49L passaged
in various mouse strains
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DISCUSSION |
In this study, we have shown that cloned lines of P. berghei ANKA can differ in their ability to induce ECM in the
same host. Unlike the polyclonal line, aliquots from the same stock of
cloned lines induced consistently similar levels of ECM in C57BL/6
mice. All of the cloned lines caused ECM, but the degree of ECM
induction was dependent on the amount of inoculum and thus differed for the cloned lines (Table 4). This finding is consistent with a previous
report showing that the amount of infectious P. berghei K173 inoculum used affects the development of ECM in
C57BL/6 mice (9). ECM is thought to develop via a complex
pathway. Grau et al. have suggested that P. berghei
ANKA antigens induce the release of IL-3, granulocyte-macrophage
colony-stimulating factor, and IFN- by CD4 Th1 cells
(20). These lymphokines activate macrophages, causing them
to release TNF-. TNF- then induces adhesion molecules (e.g.,
intracellular adhesion molecule 1) in the brain endothelium,
leading to leukocyte adhesion (14, 22, 40). Changes in the
amount of the inoculum could lead to the release of a different array
of lymphokines (e.g., IL-4 and IL-10) by activation of CD4 Th2 cells.
Consistent with this notion, we previously reported that IL-10
prevents the induction of ECM (11).
We used four cloned lines in this study. Two of these lines (1.49L and
1.97L) were derived from the same clone and differed only in the
number of passages in mice. If differences between clones can be
accounted for by antigenic differences, the differences between lines
1.49L and 1.97L showed that a clonal phenotype may not be stable. A
clone may also generate new clones after propagation. Such clonal
variation has been demonstrated for P. falciparum, in
which it occurred at a rate of 2% per generation in vitro
(39). Clonal variation is linked to the adhesion capacity of
clones and has been shown to be due to antigenic variation of a
parasite protein, PfEMP-1 (3, 42, 43). No homologous
molecules have been described for P. berghei, but
there is evidence that antigenic clonal variation exists in this
parasite species. Antigenic variation has been demonstrated by
homologous and heterologous challenges of white mice with various
clones of P. berghei ANKA (1, 2, 44).
It has been shown that the genetic background of a mouse affects the
course of parasitemia and disease (7, 12, 18, 21, 24-26, 32, 34,
38, 41). We assessed the development of ECM in six inbred mouse
strains infected with 106 PE of P. berghei ANKA cloned line 1.49L. There were marked differences in susceptibilities to ECM between the strains, but the levels of
parasitemia were similar in all of the strains (Table 5). Mice were
either susceptible or resistant to the neurological complications.
Genes in the mouse major histocompatibility complex do not seem to
control ECM susceptibility, because some mouse strains with the same
H-2d haplotype were susceptible (BALB/c) whereas
others were resistant (DBA/2). Genetic studies are required to define
precisely the role of the mouse genetic background and to identify the
genes involved in ECM resistance.
Studies with various host-parasite combinations revealed another level
of complexity. The mouse strain from which the PE were taken affected
the incidence of ECM. When the polyclonal line or cloned line 1.49L was
used, the mouse strain in which the line was passaged affected the
incidence of ECM (Tables 2 and 6). Similar findings have been reported
with another polyclonal line of P. berghei ANKA
(41). It is possible that passage of a P. berghei ANKA line in one mouse strain results in the selection of a specific group of clones which may differ from that selected in a
different mouse strain. Our data may also explain the conflicting reports on the susceptibility or resistance to ECM of BALB/c mice infected with P. berghei ANKA polyclonal lines
(15, 21, 32, 34). As these lines were passaged in different
mouse strains, they may differ in parasite clonal content. There were
also differences in the incidence of ECM in BALB/c mice obtained from
different suppliers (unpublished results). This finding suggests that
there may be differences in the genetic backgrounds of
BALB/c mice from different suppliers. Thus, different clones
could induce ECM in different mouse strains in specific combinations.
We used blood-stage parasites in this study. These parasite forms
multiply by mitosis, with mutations occurring at a very low rate. In
contrast, passage through mosquitoes may result in a large number of
new clones being created by recombination, which may occur during the
sexual stage when the parasite multiplies by meiosis. Consistent with
this idea, we were unable to induce consistently high levels of ECM in
mice through P. berghei ANKA-infected-mosquito bites or sporozoite injection (unpublished results).
In summary, the clonal composition of the parasite inoculum may affect
the incidence of ECM, and the selection of various virulent clones is
regulated by the mouse genetic background and the dynamic interplay
between the clones and their hosts. Further work is needed to
identify, at the molecular level, which P. berghei ANKA antigens are involved in the induction of ECM.
Our results also emphasize the importance of taking this phenomenon
into account in studies of pathophysiology, virulence, or protection in
rodent or human malaria.
| |
ACKNOWLEDGMENTS |
This work was partly supported by a grant from Institut
Electricité et Santé to Laurent Rénia.
We thank Ana Margarida Vigario and Georges Snounou for critical review
of the manuscript. The paper was edited by Owen Parkes.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: INSERM U445,
Institut Cochin de Génétique Moléculaire,
Hôpital Cochin, Bâtiment Gustave Roussy, 27, rue du Fg
Saint Jacques, 75014 Paris, France. Phone: 33 1 40 46 93 09. Fax: 33 1 44 07 14 25. E-mail: renia{at}icgm.cochin.inserm.fr.
Editor:
S. H. E. Kaufmann
| |
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Infection and Immunity, September 1998, p. 4093-4099, Vol. 66, No. 9
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
